Neurovascular Mechanisms of Cognitive Aging: Sex-Related Differences in the Average Progression of Arteriosclerosis, White Matter Atrophy, and Cognitive Decline.

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer's disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one's biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data ( N = 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like causality inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT) temporally precedes an acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.

Bypassing input to V1 in visual awareness: A TMS-EROS investigation.

Early visual cortex (V1-V3) is believed to be critical for normal visual awareness by providing the necessary feedforward input. However, it remains unclear whether visual awareness can occur without further involvement of early visual cortex, such as re-entrant feedback. It has been challenging to determine the importance of feedback activity to these areas because of the difficulties in dissociating this activity from the initial feedforward activity. Here, we applied single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal cortex to elicit phosphenes in the absence of direct visual input to early visual cortex. Immediate neural activity after the TMS pulse was assessed using the event-related optical signal (EROS), which can measure activity under the TMS coil without artifacts. Our results show that: 1) The activity in posterior parietal cortex 50 ms after TMS was related to phosphene awareness, and 2) Activity related to awareness was observed in a small portion of V1 140 ms after TMS, but in contrast (3) Activity in V2 was a more robust correlate of awareness. Together, these results are consistent with interactive models proposing that sustained and recurrent loops of activity between cortical areas are necessary for visual awareness to emerge. In addition, we observed phosphene-related activations of the anteromedial cuneus and lateral occipital cortex, suggesting a functional network subserving awareness comprising these regions, the parietal cortex and early visual cortex.

Development and validation of a quality control procedure for automatic segmentation of hippocampal subfields.

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two-step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between-rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross-validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within-rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas.

Fast Optical Signals for Real-Time Retinotopy and Brain Computer Interface.

A brain-computer interface (BCI) allows users to control external devices through brain activity. Portable neuroimaging techniques, such as near-infrared (NIR) imaging, are suitable for this goal. NIR imaging has been used to measure rapid changes in brain optical properties associated with neuronal activation, namely fast optical signals (FOS) with good spatiotemporal resolution. However, FOS have a low signal-to-noise ratio, limiting their BCI application. Here FOS were acquired with a frequency-domain optical system from the visual cortex during visual stimulation consisting of a rotating checkerboard wedge, flickering at 5 Hz. We used measures of photon count (Direct Current, DC light intensity) and time of flight (phase) at two NIR wavelengths (690 nm and 830 nm) combined with a machine learning approach for fast estimation of visual-field quadrant stimulation. The input features of a cross-validated support vector machine classifier were computed as the average modulus of the wavelet coherence between each channel and the average response among all channels in 512 ms time windows. An above chance performance was obtained when differentiating visual stimulation quadrants (left vs. right or top vs. bottom) with the best classification accuracy of ~63% (information transfer rate of ~6 bits/min) when classifying the superior and inferior stimulation quadrants using DC at 830 nm. The method is the first attempt to provide generalizable retinotopy classification relying on FOS, paving the way for the use of FOS in real-time BCI.

Dynamics of alpha suppression index both modality specific and general attention processes.

EEG alpha power varies under many circumstances requiring visual attention. However, mounting evidence indicates that alpha may not only serve visual processing, but also the processing of stimuli presented in other sensory modalities, including hearing. We previously showed that alpha dynamics during an auditory task vary as a function of competition from the visual modality (Clements et al., 2022) suggesting that alpha may be engaged in multimodal processing. Here we assessed the impact of allocating attention to the visual or auditory modality on alpha dynamics at parietal and occipital electrodes, during the preparatory period of a cued-conflict task. In this task, bimodal precues indicated the modality (vision, hearing) relevant to a subsequent reaction stimulus, allowing us to assess alpha during modality-specific preparation and while switching between modalities. Alpha suppression following the precue occurred in all conditions, indicating that it may reflect general preparatory mechanisms. However, we observed a switch effect when preparing to attend to the auditory modality, in which greater alpha suppression was elicited when switching to the auditory modality compared to repeating. No switch effect was evident when preparing to attend to visual information (although robust suppression did occur in both conditions). In addition, waning alpha suppression preceded error trials, irrespective of sensory modality. These findings indicate that alpha can be used to monitor the level of preparatory attention to process both visual and auditory information, and support the emerging view that alpha band activity may index a general attention control mechanism used across modalities.

Stimulus-induced changes in 1/f-like background activity in EEG.

Research into the nature of 1/f-like, non-oscillatory electrophysiological activity has grown exponentially in recent years in cognitive neuroscience. The shape of this activity has been linked to the balance between excitatory and inhibitory neural circuits, which is thought to be important for information processing. However, to date, it is not known whether the presentation of a stimulus induces changes in the parameters of 1/f activity in scalp recordings, separable from event-related potentials (ERPs). Here, we analyzed event-related broadband changes in human EEG both before and after removing ERPs to demonstrate their confounding effect, and to establish whether there are genuine stimulus-induced changes in 1/f Using data from a passive and an active auditory task (n = 23, 61% female), we found that the shape of the post-event spectra between 2-25 Hz differed significantly from the pre-event spectra even after removing the frequency-content of ERPs. Further, a significant portion of this difference could be accounted for by a rotational shift in 1/f activity, manifesting as an increase in low and a decrease in high frequencies. Importantly, the magnitude of this rotational shift was related to the attentional demands of the task. This change in 1/f is consistent with increased inhibition following stimulus onset, and likely reflects a disruption of ongoing excitatory activity proportional to processing demands. Finally, these findings contradict the central assumption of baseline normalization strategies in time-frequency analyses, namely that background EEG activity is stationary across time. As such, they have far-reaching consequences relevant for several subfields of neuroscience.SIGNIFICANCE STATEMENT:Interest in the functional role of the 1/f-like background brain activity has been growing exponentially in neuroscience. Yet, no study to date has demonstrated a clear relationship between information processing and 1/f activity by investigating event-related effects on its parameters in non-invasive recordings of neural activity. Here, we demonstrate for the first time that stimuli induce rotational changes in 1/f activity, detectable at lower frequencies and independent from the occurrence of event-related potentials. These findings suggest the presence of large-scale inhibition following stimulus onset, largest when the stimulus is novel, and indicate that the assumption of stationary background activity in the analysis of neural oscillations is untenable. These results have far-reaching consequences that cut across several subfields of neuroscience.

Recommendations and publication guidelines for studies using frequency domain and time-frequency domain analyses of neural time series.

Since its beginnings in the early 20th century, the psychophysiological study of human brain function has included research into the spectral properties of electrical and magnetic brain signals. Now, dramatic advances in digital signal processing, biophysics, and computer science have enabled increasingly sophisticated methodology for neural time series analysis. Innovations in hardware and recording techniques have further expanded the range of tools available to researchers interested in measuring, quantifying, modeling, and altering the spectral properties of neural time series. These tools are increasingly used in the field, by a growing number of researchers who vary in their training, background, and research interests. Implementation and reporting standards also vary greatly in the published literature, causing challenges for authors, readers, reviewers, and editors alike. The present report addresses this issue by providing recommendations for the use of these methods, with a focus on foundational aspects of frequency domain and time-frequency analyses. It also provides publication guidelines, which aim to (1) foster replication and scientific rigor, (2) assist new researchers who wish to enter the field of brain oscillations, and (3) facilitate communication among authors, reviewers, and editors.

Dynamics of alpha suppression and enhancement may be related to resource competition in cross-modal cortical regions.

In the face of multiple sensory streams, there may be competition for processing resources in multimodal cortical areas devoted to establishing representations. In such cases, alpha oscillations may serve to maintain the relevant representations and protect them from interference, whereas theta band activity may facilitate their updating when needed. It can be hypothesized that these oscillations would differ in response to an auditory stimulus when the eyes are open or closed, as intermodal resource competition may be more prominent in the former than in the latter case. Across two studies we investigated the role of alpha and theta power in multimodal competition using an auditory task with the eyes open and closed, respectively enabling and disabling visual processing in parallel with the incoming auditory stream. In a passive listening task (Study 1a), we found alpha suppression following a pip tone with both eyes open and closed, but subsequent alpha enhancement only with closed eyes. We replicated this eyes-closed alpha enhancement in an independent sample (Study 1b). In an active auditory oddball task (Study 2), we again observed the eyes open/eyes closed alpha pattern found in Study 1 and also demonstrated that the more attentionally demanding oddball trials elicited the largest oscillatory effects. Theta power did not interact with eye status in either study. We propose a hypothesis to account for the findings in which alpha may be endemic to multimodal cortical areas in addition to visual ones.

Characterising activity and diet compositions for dementia prevention: protocol for the ACTIVate prospective longitudinal cohort study.

INTRODUCTION: Approximately 40% of late-life dementia may be prevented by addressing modifiable risk factors, including physical activity and diet. Yet, it is currently unknown how multiple lifestyle factors interact to influence cognition. The ACTIVate Study aims to (1) explore associations between 24-hour time-use and diet compositions with changes in cognition and brain function; and (2) identify duration of time-use behaviours and the dietary compositions to optimise cognition and brain function. METHODS AND ANALYSIS: This 3-year prospective longitudinal cohort study will recruit 448 adults aged 60-70 years across Adelaide and Newcastle, Australia. Time-use data will be collected through wrist-worn activity monitors and the Multimedia Activity Recall for Children and Adults. Dietary intake will be assessed using the Australian Eating Survey food frequency questionnaire. The primary outcome will be cognitive function, assessed using the Addenbrooke's Cognitive Examination-III. Secondary outcomes include structural and functional brain measures using MRI, cerebral arterial pulse measured with diffuse optical tomography, neuroplasticity using simultaneous transcranial magnetic stimulation and electroencephalography, and electrophysiological markers of cognitive control using event-related potential and time frequency analyses. Compositional data analysis, testing for interactions between time point and compositions, will assess longitudinal associations between dependent (cognition, brain function) and independent (time-use and diet compositions) variables. CONCLUSIONS: The ACTIVate Study will be the first to examine associations between time-use and diet compositions, cognition and brain function. Our findings will inform new avenues for multidomain interventions that may more effectively account for the co-dependence between activity and diet behaviours for dementia prevention. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the University of South Australia's Human Research Ethics committee (202639). Findings will be disseminated through peer-reviewed manuscripts, conference presentations, targeted media releases and community engagement events. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12619001659190).

A healthy mind in a healthy body: Effects of arteriosclerosis and other risk factors on cognitive aging and dementia.

In this review we start from the assumption that, to fully understand cognitive aging, it is important to embrace a holistic view, integrating changes in bodily, brain, and cognitive functions. This broad view can help explain individual differences in aging trajectories and could ultimately enable prevention and remediation strategies. As the title of this review suggests, we claim that there are not only indirect but also direct effects of various organ systems on the brain, creating cascades of phenomena that strongly contribute to age-related cognitive decline. Here we focus primarily on the cerebrovascular system, because of its direct effects on brain health and close connections with the development and progression of Alzheimer's Disease and other types of dementia. We start by reviewing the main cognitive changes that are often observed in normally aging older adults, as well as the brain systems that support them. Second, we provide a brief overview of the cerebrovascular system and its known effects on brain anatomy and function, with a focus on aging. Third, we review genetic and lifestyle risk factors that may affect the cerebrovascular system and ultimately contribute to cognitive decline. Lastly, we discuss this evidence, review limitations, and point out avenues for additional research and clinical intervention.

Event-related brain potentials reveal strategy selection in younger and older adults.

It is well-established that younger adults prioritize information accrued during different stages of stimulus evaluation ("early" versus "late") to optimize performance. The extent to which older adults flexibly adjust their processing strategies, however, is largely unexplored. Twenty-four younger and twenty-four older participants completed a cued flanker task in which one of three cues, indicating the probability that a congruent array would appear (75 %, 50 %, or 25 %), was presented on each trial. Behavioral and ERP (CNV, LRP, N2, and P3b) analyses allowed us to infer cue-driven changes in strategy selection. Results indicate that when both younger and older adults expected an incongruent array, they prioritized late, target information, resulting in a decreased susceptibility to the performance-impairing effect of distractors, extending the conclusions of Gratton et al. (1992) to older adults and supporting the claim that strategic control remains largely intact during healthy aging.

Proof-of-concept evidence for trimodal simultaneous investigation of human brain function.

The link between spatial (where) and temporal (when) aspects of the neural correlates of most psychological phenomena is not clear. Elucidation of this relation, which is crucial to fully understand human brain function, requires integration across multiple brain imaging modalities and cognitive tasks that reliably modulate the engagement of the brain systems of interest. By overcoming the methodological challenges posed by simultaneous recordings, the present report provides proof-of-concept evidence for a novel approach using three complementary imaging modalities: functional magnetic resonance imaging (fMRI), event-related potentials (ERPs), and event-related optical signals (EROS). Using the emotional oddball task, a paradigm that taps into both cognitive and affective aspects of processing, we show the feasibility of capturing converging and complementary measures of brain function that are not currently attainable using traditional unimodal or other multimodal approaches. This opens up unprecedented possibilities to clarify spatiotemporal integration of brain function.

The impact of 1/f activity and baseline correction on the results and interpretation of time-frequency analyses of EEG/MEG data: A cautionary tale.

Typically, time-frequency analysis (TFA) of electrophysiological data is aimed at isolating narrowband signals (oscillatory activity) from broadband non-oscillatory (1/f) activity, so that changes in oscillatory activity resulting from experimental manipulations can be assessed. A widely used method to do this is to convert the data to the decibel (dB) scale through baseline division and log transformation. This procedure assumes that, for each frequency, sources of power (i.e., oscillations and 1/f activity) scale by the same factor relative to the baseline (multiplicative model). This assumption may be incorrect when signal and noise are independent contributors to the power spectrum (additive model). Using resting-state EEG data from 80 participants, we found that the level of 1/f activity and alpha power are not positively correlated within participants, in line with the additive but not the multiplicative model. Then, to assess the effects of dB conversion on data that violate the multiplicativity assumption, we simulated a mixed design study with one between-subject (noise level, i.e., level of 1/f activity) and one within-subject (signal amplitude, i.e., amplitude of oscillatory activity added onto the background 1/f activity) factor. The effect size of the noise level × signal amplitude interaction was examined as a function of noise difference between groups, following dB conversion. Findings revealed that dB conversion led to the over- or under-estimation of the true interaction effect when groups differing in 1/f levels were compared, and it also led to the emergence of illusory interactions when none were present. This is because signal amplitude was systematically underestimated in the noisier compared to the less noisy group. Hence, we recommend testing whether the level of 1/f activity differs across groups or conditions and using multiple baseline correction strategies to validate results if it does. Such a situation may be particularly common in aging, developmental, or clinical studies.

Spontaneous Alpha and Theta Oscillations Are Related to Complementary Aspects of Cognitive Control in Younger and Older Adults.

The resting-state human electroencephalogram (EEG) power spectrum is dominated by alpha (8-12 Hz) and theta (4-8 Hz) oscillations, and also includes non-oscillatory broadband activity inversely related to frequency (1/f activity). Gratton proposed that alpha and theta oscillations are both related to cognitive control function, though in a complementary manner. Alpha activity is hypothesized to facilitate the maintenance of representations, such as task sets in preparation for expected task conditions. In contrast, theta activity would facilitate changes in representations, such as the updating of task sets in response to unpredicted task demands. Therefore, theta should be related to reactive control (which may prompt changes in task representations), while alpha may be more relevant to proactive control (which implies the maintenance of current task representations). Less is known about the possible relationship between 1/f activity and cognitive control, which was analyzed here in an exploratory fashion. To investigate these hypothesized relationships, we recorded eyes-open and eyes-closed resting-state EEG from younger and older adults and subsequently tested their performance on a cued flanker task, expected to elicit both proactive and reactive control processes. Results showed that alpha power and 1/f offset were smaller in older than younger adults, whereas theta power did not show age-related reductions. Resting alpha power and 1/f offset were associated with proactive control processes, whereas theta power was related to reactive control as measured by the cued flanker task. All associations were present over and above the effect of age, suggesting that these resting-state EEG correlates could be indicative of trait-like individual differences in cognitive control performance, which may be already evident in younger adults, and are still similarly present in healthy older adults.

Age-related changes in cerebrovascular health and their effects on neural function and cognition: A comprehensive review.

The process of aging includes changes in cellular biology that affect local interactions between cells and their environments and eventually propagate to systemic levels. In the brain, where neurons critically depend on an efficient and dynamic supply of oxygen and glucose, age-related changes in the complex interaction between the brain parenchyma and the cerebrovasculature have effects on health and functioning that negatively impact cognition and play a role in pathology. Thus, cerebrovascular health is considered one of the main mechanisms by which a healthy lifestyle, such as habitual cardiorespiratory exercise and a healthful diet, could lead to improved cognitive outcomes with aging. This review aims at detailing how the physiology of the cerebral vascular system changes with age and how these changes lead to differential trajectories of cognitive maintenance or decline. This provides a framework for generating specific mechanistic hypotheses about the efficacy of proposed interventions and lifestyle covariates that contribute to enhanced cognitive well-being. Finally, we discuss the methodological implications of age-related changes in the cerebral vasculature for human cognitive neuroscience research and propose directions for future experiments aimed at investigating age-related changes in the relationship between physiology and cognitive mechanisms.

A wireless, skin-interfaced biosensor for cerebral hemodynamic monitoring in pediatric care.

The standard of clinical care in many pediatric and neonatal neurocritical care units involves continuous monitoring of cerebral hemodynamics using hard-wired devices that physically adhere to the skin and connect to base stations that commonly mount on an adjacent wall or stand. Risks of iatrogenic skin injuries associated with adhesives that bond such systems to the skin and entanglements of the patients and/or the healthcare professionals with the wires can impede clinical procedures and natural movements that are critical to the care, development, and recovery of pediatric patients. This paper presents a wireless, miniaturized, and mechanically soft, flexible device that supports measurements quantitatively comparable to existing clinical standards. The system features a multiphotodiode array and pair of light-emitting diodes for simultaneous monitoring of systemic and cerebral hemodynamics, with ability to measure cerebral oxygenation, heart rate, peripheral oxygenation, and potentially cerebral pulse pressure and vascular tone, through the utilization of multiwavelength reflectance-mode photoplethysmography and functional near-infrared spectroscopy. Monte Carlo optical simulations define the tissue-probing depths for source-detector distances and operating wavelengths of these systems using magnetic resonance images of the head of a representative pediatric patient to define the relevant geometries. Clinical studies on pediatric subjects with and without congenital central hypoventilation syndrome validate the feasibility for using this system in operating hospitals and define its advantages relative to established technologies. This platform has the potential to substantially enhance the quality of pediatric care across a wide range of conditions and use scenarios, not only in advanced hospital settings but also in clinics of lower- and middle-income countries.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.